[!TIP] Mnemonic: Sweat - "musk"

Sweat glands have muscarinic receptors.

pro-renin (a proenzymes) is stored in the [[Nephrology miscellaneous#Overview of renal histology and function|Juxtaglomerular cells]] of the afferent arteriole and released in response to

Thyroid hormones are stored within follicles by being bound to thyroglobulin

[!INFO] Thyroid peroxidase
Has 3 function:

1. Oxidation : I- to I2
2. Organification: Linking of I2 to tyrosine residues of thyroglobulin
3. Coupling reaction: Combination of iodinated tyrosine residues to form T3 and T4.
4. 2 x DIT = T4, DIT + MIT = T3.
   Thyroid peroxidase is the enzyme inhibited by thionamides. (Carbimazole, propylthiouracil)
   High intrathyroidal concentrations, outlasting the plasma half life.
   More inhibition of iodine organification.
   Rash: Usually can be treated with antihistamine, stoppage of thionamide not required. Cross reactivity to different thionamide seen in 50%.

• monitoring is done once weekly for the first two weeks and then monthly.

There are many recognized mutations of the enzyme and degree of dysfunction varies widely.

• Usual picture is acute episodes of haemolysis.
• Just after an attack, diagnostic investigations may be normal because the affected red cells would already have been destroyed, leaving the normal ones behind.
• Screening test: Assessment of NADPH production by UV fluorescent dye
• Confirmatory: G6PD levels (again, can be normal just after an acute episode because new reticulocytes tend to have higher levels of G6PD)Source
• Fluorescent dye test:
• 
• Source

1. appearance on blood film - cells look elliptical.

#2022GM-MAY/Q17
It is one of the 3 types of non leukemic myeloproliferative neoplasm:

• This leads to anaemia and massive splenomegaly.
• Median survival is around 5 years only! 😢
  | Primary MF | Secondary MF |
  | -------------------------------------------------------------------------------------------------------------------------------------------------------------------- | ------------------------------------------------------------ |
  | Mutation -> Activation of JAK-STAT Pathway -> increased cell production - Cont; 50% of cases are associated with JAK/STAT mutations; 25% have CALR mutation | Develops from essential thrombocythemia or polycythemia vera |
  | Increased megakaryocytes --> they secrete Fibroblast stimulating factor -> marrow fibrosis --> Extramedullary haematopoiesis | |
  | EMH isn't able to compensate for marrow loss --> pancytopaenia | |
  | Epidemiology: Middle aged and older adult; age = 67; Least common of the myeloproliferative disorders | |
  | SYmptoms: Bone pain, fever,itching, weight loss, hepatosplenomegaly (EMH), frequent infections(↓WBC), DVT, Pulmonary embolism (↑PLT) | |
  | Blood picture: Leukoerythroblastic blood picture, immature red blood cells, Marrow biopsy: initially increased cellularity, later fibrosis | |
  | FBC: leukocytosis and thrombocytosis at presentation but later leucopenia and thrombocytopenia and anaemia. | |
  | Mx: Ruxolitinib inhibits JAK STAT pathway (shown to reduce spleen size), bone marrow transplant may be curative in some, blood transfusions and Erythropoietin | |
  
  Source

⭐The Janus Associated Kinase proteins are proteins that are coupled to growth signal receptors on haematopoietic cells. When the receptors bind growth factors, they active the JAK proteins which in turn activate the STAT family of signal transducers. STAT dimers activate transcription of specific genes.

• dry tap on bone marrow aspiration
• biopsy - increased megakaryocytes
• Symptoms of anaemia
• Symptoms arising from massive splenomegaly
• "hypermatabolic" symptoms - fever, weight loss, night sweats, anorexia

2. and splenomegaly. - Ruloxitinib - oral JAK2 inhibitor; can reduce spleen size.

Aplastic anaemia

| Howell-Joly bodies | Sickle cell disease (due to hyposplenism) |
| Target cells | Hyposlenism, thalassemia, liver disease |
| Tear drop poikilocytes | myelofibrosis |

Target cells:

• They are cells with abnormally high membrane area to volume ratio.
• Seen in

1. alpha and thalassemia
2. Hyposplenism
3. liver disease

#hepatosplenomegaly

• Mimics loop diuretic use (i.e mnemonic: polyuria and polydypsia prominent in Bartter Xn)

characterized by characterized by hypokalemia, hypochloremia, metabolic alkalosis, and hyperreninemia with normal blood pressure

• "oh bee" -> "eh bee"

• The axis of the eye is not aligned with the axis of the extraocular muscles. Source-YouTube
• Therefore, elevation and depression are not controlled solely by the superior and inferior rectus. There is contribution from the obliques as well.
• To isolate the recti, the axis of the eye should be rotated away from the line of action of the obliques.
• (i.e the action of the obliques is minimized when the eye is abducted)
• Therefore, to test the eye muscles, the eye movements must be carried out as follows:
• ⭐

Anatomy of CNIII

It passes through the cerebral peduncle and red nucleus on it's way out.

• The cerebral peduncle is a structure which contains the fibers going down.
• The red nucleus is located next to the substantia nigra and is involved in motor coordination. It's red because is has haemoglobin and ferritin. Source
• lesions of the RN - cause ipsilateral flapping tremmor.
• lesions of the peduncle - contralateral hemiplegia. (because it's above the pyramidal decussation).

Posterior communicating artery aneurysm

Usually arises at the junction of the PCOM and the internal carotid (as shown above).


CNIII enters the orbit through the superior orbital fissure.

The CNIII can be affected by herniation of the temporal lobe in increased intracranial pressure.

• The superior rectus subnucleus is unique in supplying the contralateral eye muscle
• And there is a single midline nucleus supplying both levator muscles. Source

• The parasympathetic fibers originate in the Edinger-Westphal nucleus, which is located in close proximity to the occulomotor nucleus.

highly associated with malignancy, most commonly lung cancer. Source
Has a characteristic 'wood grain' appearance.

• Iron deficiency anaemia
• hyposplenism (in upto 1/3 of patients with coeliac disease)
• Tissue transglutaminase antibodies (IgA) are first line: NICE

[!INFO] Inheritance
MEN1 and MEN2 are #autosomalDominant

• Catecholamines – norepinephrine, epinephrine, and dopamine – act through ubiquitously expressed G-protein coupled adrenergic receptors and play important roles in practically every aspect of human physiology. Norepinephrine signals through α1, α2 and β1 receptors, while epinephrine will primarily stimulate only β1 and β2 receptors. At normal levels, dopamine does not have much of an effect on any of the adrenergic receptors; however, as plasma concentrations increase (ex: dopamine-secreting tumor), dopamine can stimulate both α and β receptors.
  • Symptoms include the obvious ones as well as flushing / pallor, constipation or diarrhoea and Raynaud's phenomenon, polyuria and nocturia, glycosuria, orthostatic hypotension (possibly due to fluctuation of vascular tone).
  • Dietary vanilla interferes!
  • Testing sequence: Screening as above -> plasma metanephrines , Plasma chromogranin A, Clonidine suppresssion test -> +/- Imaging (MRI, MIBG uptake scans, PET) -> genetic testing upon confirmation.
  • Anesthesia induction
  • Opiates
  • Dopamine antagonists: Eg, metoclopramide [11]
  • Cold medications
  • Beta blockers [11]
  • Drugs that inhibit catecholamine reuptake: Eg, tricyclic antidepressants and cocaine
  • Childbirth
    • Chronic alpha stimulation -> Hypertension -> compensatory salt and water loss -> hypotension during alpha blockade.
    • Because beta receptors cause vasodilation and ?attenuate the hypertension.
    • Source

Hence the lightning bolt

• Borrelia burgdoferi - spirochete.
• Has early and late features
• Then disseminates via haematogenous dissemination to various organs (heart and CNS) (patient then gets headache, neck stiffness, arthralgia, malaise)
  • ⭐If symptoms of HF AND PCWP ≥15 mmHg at rest or ≥25 mmHg during exercise => diagnosis of HF is confirmed, regardless of LVEF.

• ⭐Echo alone cannot be used to diagnose HF.
• ⭐BNP alone cannot be used to diagnose HF.
  BNP and NT-proBNP has high sensitivity and low specificity for heart failure.

• i.e If it's negative, rule out HF; if Positive, can't necessarily rule in.
  [[Statistics#Sensitivity and specificity]]

BNP - secreted by ventricles
ProBNP is converted to active BNP and inactive NT-proBNP.
(mnemonic: NT = sounds like 'inactive')
ANP and BNP secretion stimulus is high ventricular filling pressure -> therefore, increased in HF.
[!INFO] Mnemonic: HF => NTproBNP ( the one with more letters -> rises more)

• can be falsely elevated in renal failure.
• Can be normal in HF with preserved EF #2021GM-NOV/Q14

• 
  | Digoxin | Lower morbitidy, not mortality | - - - |

Preference of prescription of drugs in heart failure (HFpEF)

• Source
  Beta blockers
• HFrEF: To be used in all patients with HFrEF unless contraindicated
• HFpEF: No clear benefit.
  ACE inhibitors
• All patients with HFrEF should be given ACE inhibitors.
  Mineralocorticoid Aldosterone receptor angatonist (Spironolactone) - (MRA)
• HFrEF: (MRA) + ACEi or (MRA) + ARB are the preferred combinations
• HFpEF: Spironolactone reduces hospitalizations and probably mortality.
  • Main benefit is in EF < 35%.
    **Angiotensin receptor blockers (ARB): (Losartan)
• HFrEF: Not demonstrably superior to ACE inhibitors but have less incidence of cough and angiooedema.
• HFpEF: "ARBs should be used in HFpEF only if they are already being used to treat hypertension, diabetic kidney disease, or microalbuminuria"
  ARNI (Sacubitril valsatan):
• Should be started in all patients with stable HFrEF (particularly those with NYHA II or III symptoms and who have elevated BNP levels before treatment).
• Because neprilysin inhibitors increase BNP levels, NTproBNP levels (which are not increased by the drug) should be used instead to help diagnose and manage HF.
  SGLT-2 inhibitors
• Dapagliflozin and empagliflozin are the best studied.
• Can be used "across the ejection fraction spectrum". Source
  Diuretics:
  • Loop diuretics
  • Metolazone as add on to loop diuretics in refractory cases.
    Nitrates and dilators
• They exert beneficial haemodynamic effects by decreasing left ventricular filling pressure and systemic vascular resistance while modestly improving cardiac output.Source
• Other vasodilators such as calcium channel blockers are not used to treat LV systolic dysfunction

[!TIP] Mnemonic: first line drugs for heart failure => RBMS

• Renin antiogensin system inhibitors (Captopril / Losartan)
• Mineralocorticoid Receptor Antagonist (Spironolactone)
  - Will only work for patients in sinus rhythm
  - Evidence restricted to those with SR and rate > 70.

• ISDN + hydralazine - vasodilators

  • Used in patients intolerance of ACEi or ARB.
  • or can be adeed to ACEi/ARB if HF is refractory.
  • mechanism of nitrates:
    • Exogenous source of NO which (nitric oxide) which binds to soluble guanylate cylcase producing cyclic GMP and vascular smooth muscle relaxation.
    • Low doses -> increase venous capacitance.
    • high doses -> arteriolar vasodilation.
    • No mortality benefit (Source)
  • Mechanism of hydralazine:
    • Inhibits inositol triphosphate mediated calcium release and causes ateriolar smooth muscle relaxation.

• Vericiguat

  • oral soluble guanylate cyclase stimulator which enhances the cyclic guanosine monophosphate (GMP) pathway and sensitizes soluble guanylate cyclase to endogenous nitric oxide, resulting in pulmonary vasodilation Source
  • Evidence is retricted to those with recent worsening of heart failure
  • Can cause hypotension if given with PDE inhibitors and nitrates.

- **sodium valproate**: associated with *neural tube* defects
- **carbamazepine**: often considered the least teratogenic of the older antiepileptics
- **phenytoin**: associated with **cleft palate**

• Almost all AEDs are safe in breast feeding with the possible exception of barbiturates.